Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by circulating antinuclear autoantibodies and dysfunction of T and B lymphocytes. Both genetic and environmental factors are believed to influence development of the disease. Common lupus autoantigens show potent immunological cross-reactivities with proteins of viruses and endogenous retroviral elements. Autoantibodies to HRES-1/p28, a 28 kD nuclear protein encoded by the HRES-1 human endogenous retrovirus, were found by several laboratories in up to half of the patients with SLE and overlap syndromes (OLS). We documented molecular mimicry between HRES-1, another nuclear autoantigen, the 70K component of U1 snRNP, and infectious viral core proteins. Analysis of molecular mimicries may provide clues to the identity of viral antigens responsible for triggering cross- reactive immune responses. We detected and cloned the HRES-1 human endogenous retrovirus and mapped it to chromosome 1 at q42. We identified polymorphic genotypes in the long terminal repeat (LTR)/promoter region of the HRES-1 genomic locus and revealed their association with SLE. HRES-1 is centrally located at 1q42 with respect to microsatellite markers associated with disease susceptibility. Thus, HRES-1 or a gene in linkage disequilibrium with this genomic locus may influence autoimmunity in SLE. Genetic variations of the HRES-1 LTR may be linked to a high degree of spontaneous and 5-azacytidine-inducible fragility of the 1q42 chromosomal region. 5-azacytidine, a demethylating agent, capable of triggering autoreactivity of T cells, may influence structure and activity of the HRES-1 LTR. The specific aims will test the hypotheses that (i) identification of HRES-1 autoepitopes with regions of homology to viral proteins and other autoantigens may pinpoint pathogens responsible for initiating autoreactivities, (ii) genetic composition of the HRES-1 LTR directly or indirectly influences development of SLE, and (iii) genotypes of the LTR region determine promoter activity and expression of HRES-1/p28.